The present invention relates to a method for treatment of the airway obstruction found in chronic obstructive pulmonary disease (COPD), such as cystic fibrosis, chronic bronchitis, emphysema, and COPD where it is associated with asthma. This invention also relates to a device for carrying out the method.
Chronic obstructive pulmonary disease (COPD), which includes such entities as cystic fibrosis, chronic bronchitis, and emphysema, are steadily increasing in frequency, possibly due to continued smoking, increasing air pollution, and the continued aging of the population. It is estimated that in the United States alone, cystic fibrosis, a genetic disease, occurs in 1 of every 2500 births, that 8 million people have chronic bronchitis, and that 2 million individuals have emphysema. The number of deaths from these conditions, both from the complications of chronic disease and the results of acute attacks, are continuing to increase. The deaths from COPD rose from 33,000 in 1970 to 62,000 in 1983. This trend appears to be continuing.
COPD is characterized by edema of the mucous membrane, which lines the interior walls of the tracheobronchial tree. When the mucosa accumulates an abnormal quantity of liquid, the profuse and thickened serous fluid excreted may seriously affect ventilation in the alveoli. The mucus resists movement up the walls of the tracheobronchial tree, normally efficiently accomplished by the cilia throughout the airways. Consequently, the serous fluid can form mucus plugs, which can shut off alveoli or entire airways depriving whole sections of the lung of oxygen-rich air.
Plugs of mucus in the tracheobronchial tree may only partially block the flow of air through the bronchioles. This partial blockage can create a turbulent flow of air, which forms bubbles on the surface of mucosa. When there are enough bubbles, they become foam, which can clog airways and dramatically diminish respiration of the capillaries of the lungs.
The obstruction of the bronchi and bronchioles found in COPD is often a severely disabling condition. A wide variety of compounds are available with which physicians attempt to treat the symptoms of COPD. These compounds include oral methylxanthines, oral and inhaled beta-adrenergid agonists, inhaled cromolyn sodium, inhaled anticholinergics, and oral and inhaled corticosteroids. Despite the existence of these therapeutic tools, a large number of patients are not responsive to these medications or become non-responsive after a prolonged period of treatment.
The most common form of bronchoconstrictive disease is asthma, which is completely different from COPD. Pathologically, asthma involves constriction of the bronchioles, hypertrophy of the muscles of the bronchioles, and a characteristic infiltrate of eosinophils. Asthma is often treated with beta-adrenergic agonists. Some alpha-adrenergic receptor antagonists have been studied in man to examine their possible therapeutic utility in asthma. Barnes et al. (J. All. and Clin. Immun., 68:411-415, 1981) studied prazosin by inhalation in 10 asthmatic patients and showed that it reduced post-exercise bronchoconstriction. Gross et al. (Chest, 66:397-401, 1974) studied one asthmatic patient and found that phentolamine blocked exercise-induced bronchoconstriction when administered orally or by inhalation. On the other hand, Walden et al. (Am. Rev. Respir. Dis., 130:357-362, 1984) found in 8 asthmatics that oral phentolamine relieved bronchoconstriction in exercise-induced asthma, but not in asthma induced by ragweed. Despite these encouraging results, alphaadrenergic receptor antagonists are not currently available for the treatment of asthma by the inhalation route.
In distinction to asthma, cystic fibrosis, chronic bronchitis, and emphysema are typically treated with agents to dry up the secretions and with antibiotics to combat infection. The beta-adrenergic agonists, which work so well in the treatment of asthma, are typically ineffective for treatment of COPD. This may be a predictable result in that as the mechanisms of the diseases differ dramatically, one would not expect a successful treatment of a constriction of the bronchi and bronchioles to be applicable to a blockage of the bronchi and bronchioles. At the present time, no alpha-adrenergic receptor antagonist is available for use by the inhalation route for the treatment of any form of COPD.
There exists a need in the art for an effective treatment for chronic obstructive pulmonary diseases, such as cystic fibrosis, chronic bronchitis, and emphysema, and COPD where it is associated with asthma. The treatment should involve the use of a pharmaceutical composition that is easy to administer to a patient in need of therapy. Ideally, it should be possible for the treatment to be self-administered. In addition, there exists a need in the art for a device for the treatment of COPD.